Psychobiology Exam 2

Are there sex differences in fear conditioning?

Are there sex differences in fear conditioning?

• Females showed discrimination earlier in conditioning

• Females showed lower responding to both cues overall compared to males

• Females showed greater discrimination between CS+ and CS- overall

• men show higher learning

Why study sex differnces

To ensure that the behavioral and biomedical research (and therefore treatments and medicines) are relevant for both males and females

What are the menstrual and estrous cycles?

Low hormone: metestrus and early follicular stage

High hormone: proestrus and mid-luteal stage

Mnestrual cycle is the up and downs of hormones in humans, estrous is in rats

Do gonadal hormones influence fear extinction in females?

High level (mid luteal) of hormones show extinction recall comparable to males

Low level (early follicular) of hormones show poor extinction retention (more fear)

• Estrous cycle during conditioning or recall had no effect on learning or memory

  • Do see difference in in recall of extinction if extinction learning is given during metestrus vs proestrus

• Female rats undergoing extinction with low cycling hormones seem to show normal within-session extinction

  • They show greater fear recovery the next day (high fear/poor recall)

• High levels of sex hormones might be important for consolidation of the extinction memory

Do hormones interact with clinical status to affect fear extinction?

Level of estradiol at the time of extinction matters- no difference in startle levels for both groups when high estrogen levels (esp. PTSD group)

Females exhibit poor fear extinction ability when extinguished during low hormone phases (not matter clinical status)

Women with PTSD exhibit augmented fear responses during extinction learning and greater symptom severity during low hormone phases

Is estradiol important for fear extinction?

RIGHT AFTER IS THE BEST

No real difference in extinction learning though

The action of estradiol is time sensitive

Does manipulating estradiol levels in women change extinction?

no evidence of estradiol effect during extinction

Estradiol group showed significantly enhanced extinction recall

Looks the same as in rats (estradiol not affect actual extinction learning)

• How can we combat this?

  • Option 1: cluster exposure therapy around the time when estradiol is high- downside is that this is only once a month

  • Option 2: provide an estradiol pill as a pharmacological adjunct to exposure therapy

Is estradiol important in males?

It is not due a specific amount of estradiol across the sexes, it is relative to the sex and the body and brain to determine successful extinction retention levels

What do hormonal contraceptives do to estradiol levels?

Graham and Milad- blockade of estrogen by HCs impairs fear extinction in female rats and women

Estradiol works on negative feedback, synthetic acts to shut down natural release which will then prevent ovulation

Does HC change the efficacy of exposure therapy in phobics?

Women on HC significantly reduced approach compared to other groups (exposure therapy did not work as well)

Efficiency of completion of each stage of the graded exposure during the single exposure session

Found significant reduction in efficiency score in HC women

Does estradiol modulate brain activity during extinction in female rats?

• Low-estradiol status: appears that the vmPFC is not being sufficiently recruits for successful extinction recall

• Introducing estradiol- somehow acts to engage the vmPFC, which in turn decreases amygdala activation and allows successful extinction recall

• Higher the serum estradiol was, the greater theer extinction retention was

• Changes something in the brain that allows vmPFC to engage in recall the next day during recall

Does estradiol modulate brain activity during extinction in women?

FOR RATS AND WOMEN0 evidence that estradiol is regulating vmPFC (and human amygdala) function to alter extinction recall- in presence of extinguished cue

How does the estrous cycle impact hippocampal dendritic spines?

Significantly greater spines in hippocampus during proestrus (high levels) and fall for low

estradiol is directly responsible for the formation of dendritic spines in hippocampus- no matter the time estrogen has been gone, comes back with injection

What effect does estradiol have on dendritic spines?

Spine density peaks 2-3 days after estradiol treatment, and takes about a week to return to baseline

Estradiol is important for forming or keeping spine density in the hippocampus

Timing is funky tho because in normals estrogen cycles they decline faster

Something else causes rapid spine decline…. progesterone!

• Fear extinction is most successful when hormone and dendritic spine levels are high

  More spines, better extinction recall

What effects do estrogen and progesterone replacement following ovariectomy have on extinction?

indirect- Suggests the hormones are changing dendritic spines and altering memory fro extinction learning- not the hormonal state that matters, but the dendritic spines (altered by hormones)

Indirect evidence- suggests that findings about hormonal status mattering are possibly due to structural changes in the brain as a result of the hormones

Can reproductive experience alter extinction in females?

• Rats with no baby were typical based on cycle- less freezing for proestrus and high freezing metestrus

• rats with even just one baby- dont seem to be affected by hormonal state! same extinction in proestrus and metestrus

• Hormonal status no longer has an effect

  • Driven by something occurring as a result of pregnancy and birth (not parenting)

• not exactly the same in humans

  • negative correlation between fear recovery and estradiol levels for non mothers (Higher the estradiol levels, less fear recovery)

  • No correlation between hormone levels and extinction recall in mothers

How do the senses develop in the rat?

• Olfaction- present at birth (large in rats) and somewhat functioning

• Auditory- responding to auditory stimuli at PND10 and the external auditory meatus doesn’t open until PND 12

• Visual (final to develop)- PND 14-15 (when eyelids open in the rats)

• Sensory develops in modality-specific sequence

How early in life can we see associative fear learning?

have to use olfactory training

up to PND 6 (PND 6 rats need more training

When do specific conditioned fear responses emerge?

PND 15 is the earliest day that we will see freezing to an auditory cue

FPS can see earliest at PND 23 (after freezing)

Does the age at training, or the age at testing dictate which CRs are expressed?

Can show avoidance regardless of age

Can only express learning appropriate to when they learned

• Rats trained at PND 16 failed to show FPS, even when tested at PND 23

What does extinction look like in the developing rat?

Super extinguishers

Is there evidence for relapse phenomena (3Rs, renewal, reinstatement, and spontaneous recovery) in PND16 rat? PND23 rats?

Renewal can be seen PND23 and not PND16

Do we see fear learning in very young neonates?

Rats trained at PND10 and PND11 show evidence of conditioning compared to control rats

When does the amygdala come “online” for fear learning?

Amygdala is just not mature enough to be engaged or activated during conditioning- is engaged by PND8

Is the amygdala involved in extinction in the developing rat?

quite, seen across 12 , 17, 24

Is the mPFC involved in extinction in the developing rat?

yes but depends on the PND

at PND17- amygdala

at PND24 mPFC and amygdala

How does extinction in PND17 and PND24 rats differ?

at PND17- amygdala

at PND24 mPFC and amygdala

extinction is not context dependent at 17

What does extinction look like in adolescent rats?

Adolescents show impaired extinction recall

Extinction learning does not result in significant activation of the vmPFC

What does extinction look like in adolescent humans?

Adolescents failed to show within session extinction

• Adults showed a decrease in responding across the extinction session – confirming extinction 

• Adolescents failed to show this decrease – that is there was no evidence of within-session extinction

What is happening in the mPFC during extinction in adolescents?

• ALl ages showed good within session extinction 

• No significant differences in pMAPK+ neurons in PL 

• In the ILA, there were significantly more pMAPK+ neurons in PND24 and 70 rats

• Number of pMAPK+ neurons in PND35 rats did not differ from the No Extinction group

• Even though these 2 groups showed significant behavioral differences during the extinction session

What evidence do we have for different techniques that we can use to improve extinction in adolescents? (3 ideas)

 Giving extended extinction training

Giving a pharmacological adjunct at the time of extinction - D cycloserine

Giving a retrieval trial around the time of extinction

 Giving extended extinction training

• Extended extinction training resulted in greater within session extinction

• Extended extinction training improved extinction recall the next day 

• Extended extinction training resulted in significantly more pMAPK immunoreactive (IR) neurons in the ILA area of the mPFC

• Increasing the amount of extinction training in adolescent rats rescues long-term extinction

• This suggests that the mPFC is involved in extinction in adolescent rats and so the differences seen at this age group are quantitative rather than qualitative

Giving a pharmacological adjunct at the time of extinction - D cycloserine

A high dose of DCS immediately following extinction training enhances extinction recall

The enhancement of extinction recall by DCS is time dependent – DCS given 4 hours following extinction was ineffective 

DCS as an adjunct to extinction training was as effective as extended extinction in improving extinction recall 

Adolescents with severe anxiety may benefit from DCS enhanced CBT

• Giving a retrieval trial around the time of extinction

• In adolescent rats a retrieval-extinction procedure enhanced extinction recall 

  • prevented renewal 

• In humans, a retrieval-extinction procedure prevented any recovery of fear the next day 

  • prevented reinstatement 

• Suggests that in adolescents, a reminder cue changes the quality of the extinction learning that follows – resulting in improved extinction recall at test